What is Cytomegalovirus Corneal Endotheliitis?
Corneal endotheliitis is a specific type of inflammation in the cornea, the clear front surface of the eye. It was first identified by Khodadoust and Attarzadeh in 1982. Symptoms of this inflammation include swelling of the cornea, little white dots on the cornea (known as keratic precipitates or KP), mild inflammation in the front part of the eye (the anterior chamber), and issues with the functioning of the cornea’s inner layer (the endothelium).
This condition can show up in four forms depending on how the KP and swelling appears. These four forms are linear, sectoral, disciform, and diffuse.
Corneal endotheliitis has been linked to several viruses, including the herpes simplex virus (HSV), varicella-zoster virus (VZV), or human herpesvirus 7 (HHV-7). The cytomegalovirus (CMV) was first reported to cause corneal endotheliitis by Koizumi in 2006. If the CMV virus causes corneal endotheliitis, the individual might have the linear or coin-shaped type of KP, possibly accompanied by swelling of the cornea. This can occur in individuals with a normally functioning immune system. There may also be signs of uveitis, inflammation of the middle layer of the eye, as well as increased pressure within the eye.
What Causes Cytomegalovirus Corneal Endotheliitis?
Human Cytomegalovirus (CMV), a common type of herpes virus, is increasingly being recognized as a major cause of corneal endotheliitis, which is an inflammation of the corneal endothelium – the innermost part of the cornea. This was first noticed when CMV DNA was discovered in the fluid (aqueous humor) located in the front part of the eye in a patient with corneal endotheliitis. Additional evidence supporting this connection came from other studies.
Having a higher level of CMV in the eye fluid has been linked to a more significant loss of corneal endothelial cells and an increase in intraocular pressure, which is the pressure within the eye. Research has also shown a pattern of CMV-related inflammation in people who have had a corneal transplant.
Risk Factors and Frequency for Cytomegalovirus Corneal Endotheliitis
CMV, or cytomegalovirus, is a common virus that is associated with a person’s ethnicity, age, and socioeconomic status. This virus is found in different percentages all around the world. For instance, about half the population in the United States has it, while almost everyone in certain parts of Africa, Asia, and South America does.
Even though this virus is common worldwide, a condition caused by CMV called “endotheliitis”, which affects the eyes, is mainly reported in Asian countries. In fact, a large study in Japan, which looked at 106 cases, found that this condition is most common in middle-aged and older men. The average age of those affected was around 67 years old, and 80.2% of the men in the study had this condition.
Signs and Symptoms of Cytomegalovirus Corneal Endotheliitis
CMV endotheliitis typically affects individuals with a healthy immune system. Common symptoms patients report include sensitivity to light (photophobia) and problems with vision in one eye. A Japanese study on this condition found that several patients had a history of anterior uveitis, Posner-Schlossman syndrome, or secondary glaucoma/ocular hypertension. In addition, over half of the patients had previously undergone corneal transplantation, glaucoma surgery, or cataract surgery.
Physical symptoms can include inflamed areas (KP) on the cornea with swelling, mild inflammation inside the eye (AC), high eye pressure (ocular hypertension), a red or bloodshot eye due to inflammation (limbal injection), a condition where the iris sticks to the cornea or lens (peripheral anterior synechia), or color changes in the part of the eye that drains fluid (trabecular meshwork). The swollen areas (KP) typically resemble discs or coins and were found in 70.6% of eyes studied in the Japanese research. In 8.3% of the eyes, these swollen areas had a linear pattern.
Testing for Cytomegalovirus Corneal Endotheliitis
In simple terms, corneal endotheliitis is normally recognized through a clinical examination. It typically presents with distinctive coin-shaped marks and underlying corneal swelling, which suggests a high chance (90.9%) of this condition being caused by cytomegalovirus (CMV).
Additionally, tests can be performed on the fluid of the eye to look for signs of CMV DNA. This is usually achieved using a process called polymerase chain reaction (PCR), which can confirm a definitive diagnosis of CMV endotheliitis. A version of this test that simultaneously checks for CMV, HSV, and VZV can steer the treatment direction. If a patient still shows symptoms but tests negative for the virus, the procedure may be performed again. Research indicates a strong relationship between the amount of virus and elevated eye pressure, repeated inflammation, the presence of coin-shaped marks, and the loss of cells in the cornea.
In line with a study in Japan, typical CMV endotheliitis is identified by the presence of coin-shaped or linear impressed patterns on the cornea associated with a positive result for CMV DNA and negative results for HSV and VZV DNA. If the condition presents differently – with localized cornea swelling and signs like recurring inflammation in the front of the eye, high eye pressure or secondary glaucoma, or corneal cell loss – but still tests positive for CMV DNA and negative for HSV and VZV DNA, it’s defined as atypical CMV endotheliitis.
Tests can also be done to measure the quantity of CMV antibodies using a method known as enzyme-linked immunoassay (ELISA). A calculation called the Goldmann-Witmer coefficient helps to identify the cause of the condition. When the value of this calculation exceeds three, it suggests that the eye produces antibodies internally. Combining these tests may provide a more comprehensive diagnosis because PCR tests are only positive during the active phase of the infection, while antibody testing can detect disease at any stage.
Non-invasive imaging tests such as anterior segment optical coherence tomography (ASOCT) and in vivo confocal microscopy (IVCM), can support diagnosis and monitor how the disease progresses. For example, using ASOCT has shown a distinct pattern in the back of the cornea for people with CMV endotheliitis, which fades with antiviral treatment. Different patterns can occur based on the virus causing the endotheliitis.
In the case of CMV endotheliitis, a coin-shaped lesion often appears with a four-sided or elongated pattern. In contrast, HSV endotheliitis typically presents small, low-reflectivity protrusions, and VZV endotheliitis may show larger pigmented impressions. Owl’s eye features detected with in-vivo confocal microscopy are typically seen in CMV endotheliitis and can provide additional diagnostic information. However, it’s important to note that similar signs have been reported in HSV Keratitis and prolonged corneal transplants.
Treatment Options for Cytomegalovirus Corneal Endotheliitis
Treating CMV endotheliitis requires a combination of therapies to combat both the viral infection and inflammation. The antiviral treatment usually consists of either intravenous ganciclovir or oral valganciclovir, and could also involve topical ganciclovir. These drugs work to stop the virus from replicating its DNA. However, some drugs typically used by eye doctors for other types of viral infections, like acyclovir and valacyclovir, are not effective against CMV.
Combining this antiviral treatment with an anti-inflammatory treatment, typically topical corticosteroids, is common. It’s important to note that the corticosteroids should not be used alone. Studies have found that a mix of systemic (or whole-body) and topical (or local) treatment was more effective in reducing symptoms like corneal swelling and keratic precipitates, though it wasn’t significantly better than systemic or topical treatment alone.
There’s no agreed uniform approach to treating CMV endotheliitis with an antiviral regimen. One of the most commonly used protocols includes an oral medication called valganciclovir as the first option, with intravenous ganciclovir as a second choice if the first option fails. Maintenance doses of these drugs are then taken after the initial round of treatment has ended. Topical ganciclovir can also be used frequently during the day and then reduced to a few times a day. In cases where the constellation of symptoms is mild, only the topical treatment may be necessary.
After the condition has cleared, it is usual to stop the systemic treatment after approximately three months but continue using the topical antiviral as a preventative measure against further infection.
In situations where a patient with CMV endotheliitis has undergone a corneal transplant, it’s crucial to diagnose and treat any CMV infection quickly. Treatment is usually oral valganciclovir, either with or without the topical version of the drug, and reducing the corticosteroids as much as possible. The antiviral is typically given for six weeks to three months, after which long-term maintenance with topical ganciclovir is the norm. However, the best treatment schedules and how long to continue maintaining therapy are still being researched.
The use of topical ganciclovir alone in preventive treatment, especially for patients who have a history of CMV infection and have undergone corneal transplant surgery, could be useful, but further studies are needed. Finally, testing the eye fluid for CMV before or during a corneal transplant operation could be beneficial for those with a history of CMV infection or unexplainable endothelial failure, especially in areas where CMV infection is common.
What else can Cytomegalovirus Corneal Endotheliitis be?
Endothelial dysfunction, a type of tissue damage, can be caused by several viruses, including HSV, VZV, mumps, and the Epstein Barr virus (EBV). Different viruses can cause different symptoms: for example, HSV may lead to small to medium-sized pigmented spots, VZV might result in larger fluffy spots, and EBV could cause overall eye swelling and multiple fine spots. To confirm the diagnosis, doctors generally need to conduct a PCR test for these viruses.
There are certain types of inflammatory eye conditions, including hypertensive anterior uveitis, Fuch Uveitis syndrome, and Posner-Schlossman syndrome, which were previously thought of as having no known cause. However, recent research has suggested a strong connection between these conditions and viral infections, particularly CMV.
When it comes to patients who have received new corneas through transplantation, it can be difficult to tell the difference between corneal rejection caused by CMV and other types of rejections. Especially if the PCR test comes out negative, it can be challenging. Furthermore, treating for graft rejection might actually reactivate a dormant CMV infection, make the CMV-induced tissue damage worse, and increase the risk of graft failure. Therefore, situations such as an increase in eye pressure, graft rejection despite steroid treatment, or an unexplained sudden loss of corneal cells could indicate CMV instead of graft rejection.
What to expect with Cytomegalovirus Corneal Endotheliitis
The outlook is generally good for CMV endotheliitis if it’s caught and treated early and effectively. However, there might be recurring episodes that can lead to progressively worse outcomes. Using ganciclovir eye drops seems to help prevent a recurrence, but more research is necessary to find the best prevention strategies.
Possible Complications When Diagnosed with Cytomegalovirus Corneal Endotheliitis
CMV endotheliitis, a condition affecting the cells lining the interior of blood and lymphatic vessels, can lead to the weakening of these cells, vision loss, and secondary glaucoma, an eye condition that can cause blindness. Research in Japan showed that just over half of the eyes studied (60.6%) managed to retain clear corneas without needing additional cornea transplants.
However, systemic treatments or those affecting the whole body, like certain medications, can lead to complications. Some of these complications include pancytopenia and myelosuppression, both are conditions where your body has fewer red and white blood cells and platelets. These should be checked at regular intervals. If these conditions occur, then systemic treatments should be stopped.
Common Complications of Systemic Treatment:
- Pancytopenia
- Myelosuppression
Preventing Cytomegalovirus Corneal Endotheliitis
Patients need to understand that CMV endotheliitis, an eye inflammation, can reoccur. It’s crucial that patients follow their treatment plan carefully and watch out for signs like blurred vision, eye redness, or sensitivity to light. If treatment is delayed or the condition happens again, it can result in increasingly serious problems. Patients should also learn about the side effects of the medication used to treat CMV.
